A wide range of physiological and pathophysiological conditions are related to the renin-angiotensin system (RAS), which is an important regulator of arterial blood pressure and involves the formation and actions of several angiotensin peptides (FIG. 1). The major angiotensin peptides include the decapeptide angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu), the octapeptide angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), the heptapeptide angiotensin (1-7) (Asp-Arg-Val-Tyr-Ile-His-Pro) and the hexapeptide angiotensin IV (Val-Tyr-Ile-His-Pro-Phe).
The angiotensin peptides and the related enzymes and receptors play key roles in the cardiovascular system, the renal system, the hematopoietic system, the hepatobiliary system, the pulmonary system, the gastrointestinal system, the nervous system, and in many other critical physiological and pathophysiological pathways, in part, through stimulation of stem cell activity (FIG. 1). Renin acts on angiotensinogen to form angiotensin I (AngI), which is cleaved by angiotensin converting enzyme (ACE) to form angiotensin II (AngII), and by neutral endopeptidases to form Ang(1-7), which is also produced from AngII via cleavage by ACE2.
The three G-protein coupled receptors (GPCR) that mediate many of the actions of the angiotensin peptides are the AngII type 1 receptor (AT1R), the AngII type 2 receptor (AT2R), and the Mas receptor (Mas) known as the native receptor for Ang(1-7). The activation or deactivation of these receptors play major roles in numerous tissues, including the heart, blood vessels, liver, kidney and the brain. The development of selective antagonists for AT1R provided multiple important therapeutics for heart disease and other conditions. More recently, the elucidation of the beneficial actions of the AT2R led to selective agonists for AT2R as potential therapeutics.
This invention discloses a new class of small molecule mimetics of Ang(1-7) that are able to bind and activate the Mas receptor, and can serve as potential therapeutics for a wide range of angiotensin-related diseases. Ang(1-7) acts as an endogenous agonist of the Mas receptor, and was shown to have a number of important beneficial actions.
Ang(1-7) was shown to modulate pathways impacted by obesity and diabetes, and has been shown to exert beneficial effects in end organ damage in diabetes and hypertension (Benter et al., 2006; 2007; Singh et al., 2011). In a rat model of metabolic syndrome, elevated circulating levels of Ang(1-7) enhanced glucose tolerance, insulin sensitivity and decreased dyslipidemia (Santos et al., 2010; Marcus et al., 2012). Ang(1-7) further improves heart function in diabetic animals and after myocardial infarction and reverses diabetes-induced bone marrow suppression (Loot et al., 2002; Langeveld et al., 2008; Ebermann et al, 2008). In a Phase II clinical trial, a peptide analogue of Ang(1-7) was shown to reduce diabetic complication of non-healing foot ulcers (Balingat et al, 2012). Although this peptide may have potential use in the reduction of diabetes and insulin resistance, daily peptide injections may not be the optimal route of administration to ensure patient adherence in a chronic disease. Therefore, there remains a need for small molecule mimics of Ang(1-7) that can be effectively used to control diabetes with improved patient adherence.
Ang(1-7) and its peptide analogs are non-hypertensive regenerative factors in clinical trials for accelerating healing of hematopoietic and dermal injuries. A pharmaceutical formulation of Ang(1-7) was shown to be safe for clinical use, and was found to stimulate bone marrow and hematopoietic recovery (Rodgers et al, 2002, 2006 and Pham et al 2013). Ang(1-7) was shown to be active in several models of tissue regeneration. The actions of Ang(1-7) are hypothesized to occur through production of arachidonic acid metabolites, nitric oxide (NO), or bradykinin (BK) metabolites (Albrect 2007; Ribeirio-Olivera et al., 2008; Dias-Peixoto et al., 2008). NO is involved in protection from organ failure in diabetes and in the actions of modulators of the RAS in improved outcomes in diabetics (Kosugi et al., 2010). Ang(1-7) may also reduce end organ damage in diabetes through stimulation of PPARγ, the pathway stimulated by several therapeutics used to reduce insulin resistance in diabetes (Dhaunsi et al., 2010).
The native receptor for Ang(1-7) is the GPCR Mas, where the genetic deletion of Mas abolished Ang(1-7) binding. Accordingly, Ang(1-7) was able to bind to Mas-transfected cells and elicited arachidonic acid release. In addition, Mas KO mice do not have an anti-naturetic and water volume changes and Ang(1-7) binding in the kidney. Furthermore, Mas-deficient aortas lost their Ang(1-7)-induced relaxation response (Santos et al., 2003). The benefits of Ang(1-7) to accelerate recovery of myelosuppression and reduce chronic inflammation in diabetics are mediated through Mas.
Despite some progress and extensive efforts there is still a need for new therapeutics that might be effective in preventing diabetes, reducing diabetic complications, and treating diabetes-related conditions. The current treatment for diabetes includes the use of antidiabetic agents such as insulin, biguianides, thiazolidinediones, non-sulfonylurea secretagogues, and peptide analogs. Current treatment targets reduction of circulating glucose through supplementing insulin secretion or increase cellular sensitivity to insulin activation. Despite managing circulating glucose, the co-morbidity associated with diabetes continues, albeit at a slower progression. This includes development cardiovascular disorders such as atherosclerosis, hypertension, congestive heart failure, and cerebral ischemia. In ability to control diabetes have also been linked to other organ dysfunction including renal dysfunction, diabetic retinopathy, and neurological dysfunction. These co-morbid conditions may be a consequence of uncontrolled chronic inflammation that may be promoted by uncontrolled glucotoxicity or insulin-resistance.
Despite extensive efforts that led to the successful design and development of antagonists for the AngII receptor 1 (AT1R), known as angiotensin receptor blockers (ARBs), similar studies to identify agonists of AT2R and Mas receptors have been limited. A few notable examples are the AT2R agonist compound 21 and related compounds (Steckeling et al., 2011), the Mas agonist AVE-0991 (Santos et al., 2006), and certain Mas modulator derivatives (Zhang et al., 2012).
The discovery of effective mimetics of Ang(1-7) that activate the Mas receptor in a potent and selective manner has remained a challenge. Molecules of this type are of great interest, and are expected to find use for the treatment of several major diseases for which there is an unmed medical need.